1. The WHO Classification of Hematological Malignancies
Pathology Grand Rounds
April

2. No, it’s not that kind of Who

3. So what is it?
Classification that includes myeloid, lymphoid, histiocytic and mast cell neoplasms
applies the principles of the REAL classification to hematological neoplasms
morphology
immunophenotype
genetic features
clinical features

4. WHO classification of myeloid neoplasms
Myeloproliferative disease (MPD)
Myelodysplastic/Myeloproliferative disease
Myelodysplastic disease (MDS)
Acute myeloid leukemia (AML)
AML w/recurrent cytogenetic translocations
AML w/ myelodysplasia-related features
Therapy-related AML and MDS
AML not otherwise categorized

5. Myeloproliferative Disease
clonal stem cell disorder with “effective” hematopoiesis resulting in elevated peripheral blood cells and hepatosplenomegaly
Ph1+ CML
polycythemia vera
idiopathic myelofibrosis
essential thrombocytopenia

6. Juvenile myelomonocytic leukemia (JMML)
distinct from adult CML or CMML
classified as a MDS/MPD
lack Ph1 or BCR/ABL translocation
usually <3 years old at diagnosis
dysplasia present but not prominent

7. Chronic myelomonocytic leukemia (CMML)
some patients with MDS features - normal PMN counts, multilineage dysplasia, no organomegaly, and BM morphology of RAEB with monocytosis
some patients with MPD features - neutrophilia, monocytosis, and splenomegaly
classified as MDS/MPD

8. Atypical CML (aCML) lack Ph1 or BCR/ABL translocation
predominantly neutrophil series
dysplastic as well as proliferative features
often multilineage dysplasia
worse prognosis than Ph1+ CML
classified as MDS/MPD

9. Refractory cytopenia with multilineage dysplasia (RCMD)
RA and RARS (FAB) - dysplasia is largely limited to erythroid lineage
MDS with <5% blasts but multilineage dysplasia have worse prognosis and are more likely to die of marrow failure or progress to acute leukemia (like RAEB)
Multilineage dysplasia is defined as dysplastic features in the cells of two or more cell lines

10. What blast count should define AML?
Recent studies have shown that patients with 20-30% blasts (RAEB-T) have similar prognosis to those who have >30% blasts (AML)
WHO - AML is defined as >20% blasts
RAEB-T category dropped

11. Cytogenetic/molecular categories of AML
specific cytogenetic abnormalities do not correlate precisely with FAB categories
these should be recognized as distinct entities
include low blast count cases previously categorized as MDS (<20% blasts)
currently include four categories

12. Cytogenetic/molecular categories of AML
AML with t(8;21)(q22;q22),AML1(CBF )/ETO
Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR )
AML with abnormal bone marrow eosinophils (inv(16)(p13q22) or t(16;16)(p13;q11), CBF /MYH11X)
AML with 11q23 (MLL) abnormalities

13. Dysplasia and AML multilineage dysplasia associated with poor outcomes
dysplasia in two or more cell lines
history of prior MDS associated with poor outcomes

14. Prior therapy and AML-Alkylating agents
different from de novo AML
associated with characteristic cytogenetic alterations
3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19, 20q-, +21, t(1;7), t(2;11), and complex karyotypes
associated with a worse prognosis

15. Prior therapy and AML-Topoisomerase II inhibitors
epipodophyllotoxins and adriamycin
associated with secondary leukemias (may be lymphoid)
associated with cytogenetic abnormalities of de novo AML
11q23 (MLL), occ. t(8;21), inv(16) or t(15;17)

17. Lymphoid neoplasms
WHO adopted the REAL classification with minor modifications
split some categories
adopted some “provisional” categories as “real”

18. Lymphoblastic neoplasms
dropped FAB L1, L2, L3 terminology
ALL and lymphoblastic lymphoma single disease
group by cytogenetic abnormalities
t(9;22)(q34;q11); BCR/ABL
t(v;11q23); MLL rearranged
t(1;19)(q23;p13) E2A/PBX1
t(12;21)(p12;q22) ETV/CBF a

19. Follicular lymphoma
changed nomenclature from “follicle center lymphoma” to “follicular lymphoma”
in the rare case of a purely diffuse lymphoma of follicle center cell origin retain the term “follicle center lymphoma, diffuse”
BCL2
CD10

20. Grading follicular lymphoma
grade 1 and 2 are similar - grade 3 has earlier relapses
use Berard cell counting method for grade
grade 1: 0-5 centroblasts/hpf
grade 2: 6-15 centroblasts/hpf
grade 3: >15 centroblasts/hpf
3a - centrocytes still present
3b - no centrocytes

21. Reporting diffuse areas
should be reported and quantified as per ILSG recommendations
predominantly follicular - >75% follicular
follicular and diffuse % follicular
predominantly diffuse - <25% follicular
areas of DLBCL should be reported separately
e.g. follicular lymphoma grade 3 (75%) with DLBCL (25%)

22. Large cells in marginal zone/MALT lymphomas
recent studies suggest increased transformed cells (5-10% with clusters >20 cells) conferred a slight but significantly worse prognosis
if DLBCL coexists a separate diagnosis should be made

23. Mantle cell lymphoma mantle zone pattern is less aggressive
blastic morphology has worse prognosis
since no effective treatment morphologic subtyping is not required but encouraged for research purposes

24. Diffuse large B-cell lymphoma
no biological or clinical data to support subtyping

25. Burkitt’s vs. Burkitt’s-like lymphoma
Burkitt’s-like is a non-reproducible category
DDx - Burkitt’s and DLBCL
reserve Dx of Burkitt’s-like for high grade lymphomas
morphologically resembles Burkitt’s
has more pleomorphic or large cells than classical Burkitt’s
Ki-67 proliferative fraction >99%

26. ALCL definition ALK+ and/or t(2;5) - relatively good prognosis
not restricted to ALK + cases
ALK should be performed on all cases to the extent possible

27. Cutaneous vs. systemic ALCL
cutaneous ALCL
indolent course
lack t(2;5)(p23;q35)
ALK negative
form spectrum with lymphomatoid papulosis